Abstract 4321: A critical role for IGFBP2 in the progression and maintenance of glioma

Despite recent advances in detection methods and treatments for other tumor types, the standard of care for glioma patients remains relatively unchanged and survival rates remain dismal. Identification of key signaling nodes that function throughout glioma development will likely provide new targets for intervention. To elucidate the role of the critical oncogene, IGFBP2, in the progression and maintenance of glioma, we generated an inducible mouse model. This model utilizes the RCAS/Tv-a system, which places the Tv-a receptor for the avian RCAS virus under the control of the Nestin promoter to drive Tv-a expression in glial progenitors. The RCAS virus, expressing the desired oncogenes, infects Tv-a expressing cells and delivers the oncogene. By using RCAS to express a tetracycline-responsive IGFBP2 and a tetracycline transactivator, we can modify this system to generate an inducible IGFBP2 model. Using this model, we have tested the hypothesis that IGFBP2 is a key target for glioma therapy due to its important role in glioma maintenance. The studies described here aim to: (1) determine the effects of delayed IGFBP2 expression on the progression of PDGFB-induced, low-grade gliomas; and (2) determine whether continued expression of IGFBP2 is required to maintain the high-grade nature of gliomas induced by the co-expression of PDGFB and IGFBP2. Previously, our lab and others determined that over-expression of PDGFB in glial progenitors led to the development of low-grade glioma. Our lab also determined that IGFBP2 cooperates with PDGFB to promote progression to high-grade glioma. In the inducible model system, tetracycline-mediated IGFBP2 induction in vivo was confirmed by both quantitative RT-PCR of mouse brain tissue and serum ELISA, indicating that RCAS-delivered IGFBP2 is both expressed and secreted upon induction. IGFBP2 induction from birth increased the proportion of tumors that progressed to high-grade glioma, whereas delayed IGFBP2 induction led to later onset of high-grade tumor development. Significantly, there was a decrease in tumor-free survival upon IGFBP2 induction. This is consistent with analysis of transcriptome data from the Rembrandt and TCGA databases. These studies validate an important role for IGFBP2 in the progression of glioma. Ongoing studies using the inducible system are exploring the response of high-grade gliomas to sustained and brief inactivation of IGFBP2. Elucidating the roles of IGFPB2 in glioma progression and maintenance will provide critical information pertinent to the design and implementation of future therapies to target this molecule or associated signaling pathways, as well as how IGFBP2 might be useful as a marker for disease state. Further, these studies may have a more global impact on cancer research as IGFBP2 over-expression has also been associated with other high-grade tumors such as prostate and breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4321. doi:10.1158/1538-7445.AM2011-4321